The ability of tumors to grow beyond a few cubic millimeters in volume depends on the formation of new blood vessels within the microenvironment of the tumors (Ferrara, N. Nat Rev Cancer, 2002, 2:795-803; Kerbel, R. S. Carcinogenesis, 2000, 21:505-15; Carmeliet, P. and Jain, R. K. Nature, 2000, 407:249-57; Yancopoulos, G. D. et al. Nature, 2000, 407:242-8). This angiogenic process is triggered by several key growth factors that are secreted by the tumor. The growth factors not only bind their receptors on endothelial cells and stimulate their proliferation initiating new blood vessel formation, but also bind receptors on accessory cells such as pericytes that maintain vessel integrity (Ferrara, N. Nat Rev Cancer, 2002, 2:795-803; Kerbel, R. S. Carcinogenesis, 2000, 21:505-15; Carmeliet, P. and Jain, R. K. Nature, 2000, 407:249-57; Yancopoulos, G. D. et al. Nature, 2000, 407:242-8; Helmlinger, G., et al. Nat Med, 1997, 3:177-82; Holash, J. et al. Science, 1999, 284:1994-8). Among the most studied growth factors are vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Several studies have demonstrated the participation of these two growth factors in the angiogenic process with VEGF playing a key role mainly in the initiation of the formation of new blood vessels and PDGF being involved in the maintenance of these vessels (Bergers, G. et al. J Clin Invest, 2003, 111:1287-95; Dvorak, H. F. J Clin Oncol, 2002, 20:4368-80; Ferrara, N. Curr Top Microbiol Immunol, 1999, 237:1-30; Dvorak, H. F. et al. Curr Top Microbiol Immunol, 1999, 237:97-132; Eriksson, U. and Alitalo, K. Curr Top Microbiol Immunol, 1999, 237:41-57).
This observation prompted an interest in designing strategies to suppress the functions of VEGF and PDGF, with the ultimate goal of inhibiting angiogenesis and starving tumors. The approaches that have been taken were based on targeting the biochemical steps involved in the mechanism of action of these growth factors. These include inhibiting the binding of VEGF and PDGF to their respective receptors by using antibodies against the growth factors. One of these, AVASTIN, which targets VEGF, has recently been approved for clinical use in patients with metastatic colorectal cancer (Zhang, W. et al. Angiogenesis, 2002, 5:35-44; Ferrara, N. Semin Oncol, 2002, 29:10-4). Another approach has involved the development of inhibitors of the tyrosine kinase activities of the PDGF and VEGF receptors, resulting in suppression of the downstream signal transduction pathways triggered by these growth factors (Kerbel, R. S. Carcinogenesis, 2000, 21:505-15; Jain, R. K. Semin Oncol, 2002, 29:3-9; Morin, M. J. Oncogene, 2000, 19:6574-83; Miao, R. Q. et al. Blood, 2002, 100:3245-52; Laird, A. D. et al. Cancer Res, 2000, 60:4152-60; Wedge, S. R. et al. Cancer Res, 2000, 60:970-5). Most of these agents mimic the structure of ATP and some are potent antitumor agents that are presently in clinical trials. However, none have been approved yet by the FDA.
The approval by the FDA of AVASTIN (bevacizumab), which increases by 5 months the median survival of patients with metastatic colorectal cancer, further validates targeting angiogenic processes as a strategy to treat cancer (Ferrara, N. Semin Oncol, 2002, 29:10-4). However, much more needs to be done to fully exploit this approach. For example, in other clinical trials, AVASTIN failed to prolong the lives of patients with metastatic breast cancer. One possible explanation for this inconsistent activity is that advanced metastatic breast cancer may circumvent anti-VEGF angiogenesis therapy by means of other growth factors. Indeed support for this suggestion comes from preclinical studies showing that early breast cancer secretes mainly VEGF whereas advanced breast cancer secretes additional growth factors (Relf, M. et al. Cancer Res, 1997, 57:963-9). Furthermore, in an animal pancreatic cancer model, SU5416, a VEGF receptor tyrosine kinase inhibitor suppresses early, but not late, development of pancreatic tumors. More importantly in the same model, treatment with SU6668 (which inhibits both VEGF and PDGF receptor tyrosine kinases) induced regression of advanced pancreatic tumor at late stage of development (Bergers, G. et al. J Clin Invest, 2003, 111:1287-95) suggesting that the failure of anti-VEGF therapy may be due to its ability to inhibit only initiation but not maintenance of blood vessels. Further support for this suggestion comes from a very recent study where AVASTIN inhibited the formation of new blood vessels but was ineffective at inhibiting already established ones in an animal model where neuroblastoma cells were transplanted onto mouse kidneys (Huang, J. et al. Proc Natl Acad Sci USA, 2003, 100:7785-90). Taken together, the present understanding of the angiogenesis process suggests that simultaneously targeting of growth factors that initiate (i.e., VEGF) as well as those that maintain (i.e., PDGF) blood vessels may be a more effective approach to cancer therapy than targeting only one growth factor.